Journal
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR AND CELL BIOLOGY OF LIPIDS
Volume 1530, Issue 2-3, Pages 134-145Publisher
ELSEVIER
DOI: 10.1016/S1388-1981(00)00174-8
Keywords
liposome; drug delivery system; interferon-gamma; biodistribution; subcutaneous administration
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Interferon-gamma (IFN gamma) has proven to be a promising adjuvant in vaccines against cancer and infectious diseases. However, due to its rapid biodegradation and clearance, its efficacy is severely reduced. Liposomal association might prolong the residence time of IFN gamma, but no efforts have been made to optimize the biopharmaceutical characteristics of liposomal IFN gamma for its application in therapy or as vaccine immunoadjuvant. In the present study, various liposomal formulations of recombinant human IFN gamma (hIFN gamma), differing in lipid composition, were prepared via the film hydration method and characterized in vitro regarding association efficiency and bioactivity, and in vivo regarding cytokine release kinetics after subcutaneous (s.c.) administration into mice. Human IFN gamma, can be formulated in large, multilamellar liposomes with high association efficiency (> 80%) and preservation of bioactivity. A critical parameter is the inclusion of negatively charged phospholipids to obtain a high liposome association efficiency, which is dominated by electrostatic interactions. The fraction of externally adsorbed protein compared to the total associated protein call be minimized from 74+/-9% to 8+/-3% by increasing the ionic strength of the dispersion medium. After injection of free I-125-hIFN gamma, the radiolabel was detectable up to 48 h at the injection site. Liposomal encapsulation of I-125-hIFN gamma increased the local area under the curve 4-fold, and the presence of the radiolabeled hIFN gamma at the injection site was prolonged to 7 days. The release kinetics and overall residence time of the cytokine at the s.c. administration site was influenced by depletion of the externally adsorbed IFN gamma, reducing the initial burst release. Increasing the rigidity of the liposome bilayer also resulted in a more pronounced reduction of the burst release and a 19-fold increase in the residence time of the protein at the s.c. administration site, compared to the free cytokine. As adjuvanticity of liposomal IFN gamma may strongly depend on the release kinetics of cytokines in vivo, the findings in this paper may contribute to a rational design of liposomal-cytokine adjuvants in vaccines against cancer and infectious diseases. (C) 2001 Elsevier Science B.V. All rights reserved.
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